The SNRP-1 Program at UCC is centered around three research topics: norepinephrine modulation of sensitization to cocaine, neuroprotection by nicotine and tobacco cembranoids, and cembranoid mechanism of action on nicotinic receptors. A Natural Products Core provides tobacco and marine cembranoids, both known and new. Each project is performed in collaboration with a collaborator from a research-intensive institution: UCLA, Cornell U. (Ithaca) and the Vollum Institute (OHSU). SNRP-1 was funded since October 1999. Four RO1 proposals were presented to the NIH during the third year, three of which are now in the process of re-submission. Thirty nine manuscripts were published in peer-reviewed journals. Among the scientific discoveries reported, we would like to mention the following: 1) Noradrenergic transmission through alpha-2 receptors mediates some of the inhibitory effects of cocaine in the prefrontal cortex. 2) Both nicotine and tobacco cembranoids protect the hippocampal slice from NMDA-induced excitotoxicity, but the signal transduction pathways are different. 3) Cembranoids are nicotinic antagonists whose inhibitory action can be released by certain cocaine derivatives. We now propose to continue this successful program for a second cycle of five years. Three new scientists will address the issues of oxidative damage in Huntington disease, direct effects of thyroid hormones on the nAChR and on synapse remodelling, and modulation of potassium channels by spermine. Collaborators are from Washington University and UCLA. Program activities include seminars, courses, travel, etc. A transition plan from SNRP-1 to RO1 funding, is proposed for the present investigators. A plan to attract Puerto Rican Ph.Ds to postdoctoral positions with SNRP scientists at UCC is also presented.